tbuckley/cabot-search huggingface dataset:
Outcome of untreated low-level viremia versus antiviral therapy-induced or spontaneous undetectable HBV-DNA in compensated cirrhosis
Authors: Daniel Q. Huang, Nobuharu Tamaki, Hyung Woong Lee, Soo Young Park, Yu Rim Lee, Hye Won Lee, Seng Gee Lim, Tae Seop Lim, Masayuki Kurosaki, Hiroyuki Marusawa, Toshie Mashiba, Masahiko Kondo, Yasushi Uchida, Haruhiko Kobashi, Koichiro Furuta, Namiki Izumi, Beom Kyung Kim, Dong Hyun Sinn
Journal: Hepatology (2023)

Background: Comparative outcomes of HBV-infected compensated cirrhosis with low-level viremia (LLV) versus maintained virological response (MVR) are unclear. We conducted a large, multiethnic, multicenter study to examine the natural history of LLV versus MVR in compensated cirrhosis. Patients and Methods: We enrolled patients with HBV-infected compensated cirrhosis (n=2316) from 19 hospitals in South Korea, Singapore, and Japan. We defined the LLV group as untreated patients with ≥1 detectable serum HBV-DNA (20–2000 IU/mL), Spontaneous-MVR group as untreated patients with spontaneously achieved MVR, and antiviral therapy (AVT)-MVR group as patients achieving AVT-induced MVR. Study end points were HCC or hepatic decompensation. Results: The annual HCC incidence was 2.7/100 person-years (PYs), 2.6/100 PYs, and 3.3/100 PYs for LLV (n=742), Spontaneous-MVR (n=333), and AVT-MVR (n=1241) groups, respectively ( p = 0.81 between LLV vs. Spontaneous-MVR groups and p = 0.37 between LLV vs. AVT-MVR groups). Similarly, the annual decompensation incidence was 1.6/100 PYs, 1.9/100 PYs, and 1.6/100 PYs for LLV, Spontaneous-MVR, and AVT-MVR groups, respectively ( p = 0.40 between LLV vs. Spontaneous-MVR groups and p = 0.83 between LLV vs. AVT-MVR groups). Multivariable analyses determined that HCC and decompensation risks in the LLV group were comparable to those with Spontaneous-MVR and AVT-MVR groups (all p &gt;0.05). Propensity score matching also reproduced similar results for HCC and decompensation risks (all p &gt;0.05 between LLV vs. Spontaneous-MVR groups and between LLV vs. AVT-MVR groups). Conclusions: Untreated LLV in HBV-infected compensated cirrhosis is not associated with increased risk of disease progression compared with Spontaneous-MVR and AVT-MVR. These data have important implications for practice and further research.
Cholera Outbreak — Haiti, September 2022–January 2023
Authors: Denisse Vega Ocasio, Stanley Juin, David Berendes, Kristen Heitzinger, Graeme Prentice-Mott, Anne Marie Desormeaux, Phaimyr D. Jn Charles, Jonas Rigodon, Valerie Pelletier, Reginald Jean Louis, John Vertefeuille, Jacques Boncy, Gerard Joseph, Valusnor Compère, Donald Lafontant, Lesly L. Andrecy, Edwige Michel, Katilla Pierre, Evenel Thermidor, David Fitter, Yoran Grant-Greene, Matthew Lozier, Samson Marseille, Ashley Andujar, Alondra Baez-Nieves, Lucy Breakwell, Sara Breese, Joan Brunkard, Mushtaq Dualeh, Thomas Handzel, Christine Lee, Andrea Martinsen, Taylor Osborne, David Shih, Amanda Tiffany, Maryann Turnsek
Journal: MMWR Morbidity and Mortality Weekly Report (2023)

On September 30, 2022, after >3 years with no confirmed cholera cases (1), the Directorate of Epidemiology, Laboratories and Research (DELR) of the Haitian Ministry of Public Health and Population (Ministère de la Santé Publique et de la Population [MSPP]) was notified of two patients with acute, watery diarrhea in the metropolitan area of Port-au-Prince. Within 2 days, Haiti's National Public Health Laboratory confirmed the bacterium Vibrio cholerae O1 in specimens from the two patients with suspected cholera infection, and an outbreak investigation began immediately. As of January 3, 2023, >20,000 suspected cholera cases had been reported throughout the country, and 79% of patients have been hospitalized. The moving 14-day case fatality ratio (CFR) was 3.0%. Cholera, which is transmitted through ingestion of water or food contaminated with fecal matter, can cause acute, severe, watery diarrhea that can rapidly lead to dehydration, shock, and death if not treated promptly (2). Haiti is currently facing ongoing worsening of gang violence, population displacement, social unrest, and insecurity, particularly in the metropolitan area of Port-au-Prince, including Belair, Bas-Delmas, Centre-Ville, Martissant, Cité Soleil, Croix-des Bouquets, and Tabarre, creating an environment that has facilitated the current resurgence of cholera (3). This report describes the initial investigation, ongoing outbreak, and public health response to cholera in Haiti. Cholera outbreak responses require a multipronged, multisectoral approach including surveillance; case management; access to safe water, sanitation, and hygiene (WASH) services; targeted oral cholera vaccine (OCV) campaigns; risk communication; and community engagement. This activity was reviewed by CDC and was conducted consistent with applicable federal law and CDC policy.
Reduced methylation correlates with diabetic nephropathy risk in type 1 diabetes
Authors: Ishant Khurana, Harikrishnan Kaipananickal, Scott Maxwell, Sørine Birkelund, Anna Syreeni, Carol Forsblom, Jun Okabe, Mark Ziemann, Antony Kaspi, Haloom Rafehi, Anne Jørgensen, Keith Al-Hasani, Merlin C. Thomas, Guozhi Jiang, Andrea O.Y. Luk, Heung Man Lee, Yu Huang, Yotsapon Thewjitcharoen, Soontaree Nakasatien, Thep Himathongkam, Christopher Fogarty, Rachel Njeim, Assaad Eid, Tine Willum Hansen, Nete Tofte, Evy C. Ottesen, Ronald C.W. Ma, Juliana C.N. Chan, Mark E. Cooper, Peter Rossing, Per-Henrik Groop, Assam El-Osta
Journal: Journal of Clinical Investigation (2023)

Diabetic nephropathy (DN) is a polygenic disorder with few risk variants showing robust replication in large-scale genome-wide association studies. To understand the role of DNA methylation, it is important to have the prevailing genomic view to distinguish key sequence elements that influence gene expression. This is particularly challenging for DN because genome-wide methylation patterns are poorly defined. While methylation is known to alter gene expression, the importance of this causal relationship is obscured by array-based technologies since coverage outside promoter regions is low. To overcome these challenges, we performed methylation sequencing using leukocytes derived from participants of the Finnish Diabetic Nephropathy (FinnDiane) type 1 diabetes (T1D) study (n = 39) that was subsequently replicated in a larger validation cohort (n = 296). Gene body-related regions made up more than 60% of the methylation differences and emphasized the importance of methylation sequencing. We observed differentially methylated genes associated with DN in 3 independent T1D registries originating from Denmark (n = 445), Hong Kong (n = 107), and Thailand (n = 130). Reduced DNA methylation at CTCF and Pol2B sites was tightly connected with DN pathways that include insulin signaling, lipid metabolism, and fibrosis. To define the pathophysiological significance of these population findings, methylation indices were assessed in human renal cells such as podocytes and proximal convoluted tubule cells. The expression of core genes was associated with reduced methylation, elevated CTCF and Pol2B binding, and the activation of insulin-signaling phosphoproteins in hyperglycemic cells. These experimental observations also closely parallel methylation-mediated regulation in human macrophages and vascular endothelial cells.
Scavenger receptor a is a major homeostatic regulator that restrains drug-induced liver injury
Authors: Chunqing Guo, Wenjie Liu, Zheng Liu, Jinyang Cai, Xiaofei Yu, Hongxia Wang, Xia Li, Daming Zuo, Xixian Jiang, Bei Zhang, Jinze Liu, Arun J. Sanyal, Puneet Puri, Huiping Zhou, Xiang-Yang Wang
Journal: Hepatology (2023)

Background and Aim: Drug-induced liver injury occurs frequently and can be life threatening. Although drug-induced liver injury is mainly caused by the direct drug cytotoxicity, increasing evidence suggests that the interplay between hepatocytes and immune cells can define this pathogenic process. Here, we interrogate the role of the pattern recognition scavenger receptor A (SRA) for regulating hepatic inflammation and drug-induced liver injury. Approach and Results: Using acetaminophen (APAP) or halothane-induced liver injury models, we showed that SRA loss renders mice highly susceptible to drug hepatotoxicity, indicated by the increased mortality and liver pathology. Mechanistic studies revealed that APAP-induced liver injury exaggerated in the absence of SRA was associated with the decreased anti-inflammatory and prosurvival cytokine IL-10 concomitant with excessive hepatic inflammation. The similar correlation between SRA and IL-10 expression was also seen in human following APAP uptake. Bone marrow reconstitution and liposomal clodronate depletion studies established that the hepatoprotective activity of SRA mostly resized in the immune sentinel KCs. Furthermore, SRA-facilitated IL-10 production by KCs in response to injured hepatocytes mitigated activation of the Jun N-terminal kinase-mediated signaling pathway in hepatocytes. In addition, supplemental use of IL-10 with N -acetylcysteine, only approved treatment of APAP overdose, conferred mice improved protection from APAP-induced liver injury. Conclusion: We identify a novel hepatocyte-extrinsic pathway governed by the immune receptor SRA that maintains liver homeostasis upon drug insult. Giving that drug (ie, APAP) overdose is the leading cause of acute liver failure, targeting this hepatoprotective SRA-IL-10 axis may provide new opportunities to optimize the current management of drug-induced liver injury.
Hypothalamic-pituitary-gonadal function, pubertal development, and fertility outcomes in male and female medulloblastoma survivors: a single-center experience
Authors: Eve Stern, Michal Ben-Ami, Noah  Gruber, Amos Toren, Shani Caspi, Gadi Abebe-Campino, Michal Lurye, Michal Yalon, Dalit Modan-Moses
Journal: Neuro-Oncology (2023)

Abstract Background Endocrine deficiencies, including hypothalamic-pituitary-gonadal axis (HPGA) impairment, are common in survivors of childhood and adolescent medulloblastoma. Still, data regarding pubertal development and fecundity are limited, and few studies assessed HPGA function in males. We aimed to describe HPGA function in a large cohort of patients with medulloblastoma. Methods A retrospective study comprising all 62 medulloblastoma patients treated in our center between 1987 and 2021, who were at least 2 years from completion of therapy. HPGA function was assessed based on clinical data, biochemical markers, and questionnaires. Results Overall, 76% of female patients had clinical or biochemical evidence of HPGA dysfunction. Biochemical evidence of diminished ovarian reserve was seen in all prepubertal girls (n = 4). Among the males, 34% had clinical or biochemical evidence of gonadal dysfunction, 34% had normal function, and 29% were age-appropriately clinically and biochemically prepubertal. The difference between males and females was significant (P = .003). Cyclophosphamide-equivalent dose was significantly associated with HPGA function in females, but not in males. There was no association between HPGA dysfunction and other endocrine deficiencies, length of follow-up, weight status, and radiation treatment protocol. Two female and 2 male patients achieved successful pregnancies, resulting in 6 live births. Conclusions HPGA dysfunction is common after treatment for childhood medulloblastoma. This is seen more in females, likely due to damage to the ovaries from spinal radiotherapy. Our findings may assist in counseling patients and their families regarding risk to future fertility and need for fertility preservation.
Nicotinamide N-methyltransferase promotes M2 macrophage polarization by IL6 and MDSC conversion by GM-CSF in gallbladder carcinoma
Authors: Yang Li, Bo Yang, Huijie Miao, Liguo Liu, Ziyi Wang, Chengkai Jiang, Yang Yang, Shimei Qiu, Xuechuan Li, Yajun Geng, Yijian Zhang, Yingbin Liu
Journal: Hepatology (2023)

Background and Aims: Nicotinamide N-methyltransferase (NNMT), an enzyme responsible for the methylation of nicotinamide, is involved in many metabolic pathways in adipose tissue and the liver. However, the role of NNMT in editing the tumor immune microenvironment is not well understood. Approach and Results: Here, we identified that NNMT can promote IL6 and granulocyte-macrophage colony-stimulating factor (GM-CSF) expression by decreasing the tri-methyl-histone H3 levels on the promoters of IL6 and CSF2 (encoding GM-CSF) and CCAAT/Enhancer Binding Protein, an essential transcription factor for IL6 expression, thus promoting differentiation of macrophages into M2 type tumor-associated macrophages and generation of myeloid-derived suppressor cells from peripheral blood mononuclear cells. Treatment of xenografted tumor models overexpressing NNMT gallbladder carcinoma (GBC) cells with the NNMT inhibitor JBSNF-000088 resulted in compromised tumor development and decreased expression levels of IL6, GM-CSF, tumor-associated macrophage marker CD206, and myeloid-derived suppressor cell marker CD33 but increased expression levels of CD8. In addition, elevated expression of NNMT in tumors of patients with GBC was correlated with increased expression levels of CD206 and CD33 but with decreased levels of CD8 and survival of patients. Conclusions: These data highlight the critical role of NNMT in GBC progression. Inhibition of NNMT by JBSNF-000088 is a potential molecular target for GBC immunotherapy. Export
Any alcohol use in NAFLD patients is associated with significant changes to the intestinal virome
Authors: Cynthia L. Hsu, Sonja Lang, Münevver Demir, Derrick E. Fouts, Peter Stärkel, Bernd Schnabl
Journal: Hepatology (2023)

The prevalence of alcohol use disorder (AUD) and metabolic dysfunction-associated fatty liver disease (MAFLD) are increasing worldwide, leading to the increasing likelihood of both etiologies contributing to a patient's liver disease. However, the effects of modest alcohol use in NAFLD are controversial and more studies are needed. We compared the intestinal viromes of patients with AUD and NAFLD in order to evaluate the effect of alcohol consumption on the intestinal viromes of NAFLD patients by extracting virus-like particles and performing metagenomic sequencing.
Cancer statistics, 2023
Authors: Rebecca L. Siegel, Kimberly D. Miller, Nikita Sandeep Wagle, Ahmedin Jemal
Journal: CA A Cancer Journal for Clinicians (2023)

Each year, the American Cancer Society estimates the numbers of new cancer cases and deaths in the United States and compiles the most recent data on population-based cancer occurrence and outcomes using incidence data collected by central cancer registries and mortality data collected by the National Center for Health Statistics. In 2023, 1,958,310 new cancer cases and 609,820 cancer deaths are projected to occur in the United States. Cancer incidence increased for prostate cancer by 3% annually from 2014 through 2019 after two decades of decline, translating to an additional 99,000 new cases; otherwise, however, incidence trends were more favorable in men compared to women. For example, lung cancer in women decreased at one half the pace of men (1.1% vs. 2.6% annually) from 2015 through 2019, and breast and uterine corpus cancers continued to increase, as did liver cancer and melanoma, both of which stabilized in men aged 50 years and older and declined in younger men. However, a 65% drop in cervical cancer incidence during 2012 through 2019 among women in their early 20s, the first cohort to receive the human papillomavirus vaccine, foreshadows steep reductions in the burden of human papillomavirus-associated cancers, the majority of which occur in women. Despite the pandemic, and in contrast with other leading causes of death, the cancer death rate continued to decline from 2019 to 2020 (by 1.5%), contributing to a 33% overall reduction since 1991 and an estimated 3.8 million deaths averted. This progress increasingly reflects advances in treatment, which are particularly evident in the rapid declines in mortality (approximately 2% annually during 2016 through 2020) for leukemia, melanoma, and kidney cancer, despite stable/increasing incidence, and accelerated declines for lung cancer. In summary, although cancer mortality rates continue to decline, future progress may be attenuated by rising incidence for breast, prostate, and uterine corpus cancers, which also happen to have the largest racial disparities in mortality.
Early infancy dysbiosis in food protein‐induced enterocolitis syndrome: A prospective cohort study
Authors: Kuan‐Wen Su, Murat Cetinbas, Victoria M. Martin, Yamini V. Virkud, Hannah Seay, Renata Ndahayo, Rachael Rosow, Michael Elkort, Brinda Gupta, Eileen Kramer, Tetiana Pronchick, Susan Reuter, Ruslan I. Sadreyev, Jing‐Long Huang, Wayne G. Shreffler, Qian Yuan
Journal: Allergy (2023)

Abstract Background The microbiome associations of food protein‐induced enterocolitis syndrome (FPIES) are understudied. We sought to prospectively define the clinical features of FPIES in a birth cohort, and investigate for the evidence of gut dysbiosis. Methods We identified children diagnosed with FPIES in the Gastrointestinal Microbiome and Allergic Proctocolitis Study, a healthy infant cohort. Children were assessed and stools were collected at each well child visit. The clinical features of the children with FPIES were summarized. Stool microbiome was analyzed using 16S rRNA sequencing comparing children with and without FPIES. Results Of the 874 children followed up for 3 years, 8 FPIES cases (4 male) were identified, yielding a cumulative incidence of 0.92%. The most common triggers were oat and rice ( n = 3, each) followed by milk ( n = 2). The children with FPIES were more likely to have family history of food allergy (50% vs. 15.9% among unaffected, p = .03). The average age of disease presentation was 6 months old. During the first 6 months of life, stool from children with FPIES contained significantly less Bifidobacterium adolescentis , but more pathobionts, including Bacteroides spp. (especially Bacteroides fragilis ), Holdemania spp., Lachnobacterium spp., and Acinetobacter lwoffii . The short‐chain fatty acid (SCFA)‐producing Bifidobacterium shunt was expressed significantly less in the stool from FPIES children. Conclusions In this cohort, the cumulative incidence over the 3‐year study period was 0.92%. During the first 6 months of life, children with FPIES had evidence of dysbiosis and SCFA production pathway was expressed less in their stool, which may play an important role in the pathogenesis of FPIES.
STRA6 is essential for induction of vascular smooth muscle lineages in human embryonic cardiac outflow tract development
Authors: Chikai Zhou, Timm Häneke, Eduarde Rohner, Jesper Sohlmér, Polina Kameneva, Artem Artemov, Igor Adameyko, Makoto Sahara
Journal: Cardiovascular Research (2023)

Abstract Aims Retinoic acid (RA) signalling is essential for heart development, and dysregulation of the RA signalling can cause several types of cardiac outflow tract (OFT) defects, the most frequent congenital heart disease (CHD) in humans. Matthew-Wood syndrome is caused by inactivating mutations of a transmembrane protein gene STRA6 that transports vitamin A (retinol) from extracellular into intracellular spaces. This syndrome shows a broad spectrum of malformations including CHD, although murine Stra6-null neonates did not exhibit overt heart defects. Thus, the detailed mechanisms by which STRA6 mutations could lead to cardiac malformations in humans remain unclear. Here, we investigated the role of STRA6 in the context of human cardiogenesis and CHD. Methods and results To gain molecular signatures in species-specific cardiac development, we first compared single-cell RNA sequencing (RNA-seq) datasets, uniquely obtained from human and murine embryonic hearts. We found that while STRA6 mRNA was much less frequently expressed in murine embryonic heart cells derived from the Mesp1+ lineage tracing mice (Mesp1Cre/+; Rosa26tdTomato), it was expressed predominantly in the OFT region-specific heart progenitors in human developing hearts. Next, we revealed that STRA6-knockout human embryonic stem cells (hESCs) could differentiate into cardiomyocytes similarly to wild-type hESCs, but could not differentiate properly into mesodermal nor neural crest cell-derived smooth muscle cells (SMCs) in vitro. This is supported by the population RNA-seq data showing down-regulation of the SMC-related genes in the STRA6-knockout hESC-derived cells. Further, through machinery assays, we identified the previously unrecognized interaction between RA nuclear receptors RARα/RXRα and TBX1, an OFT-specific cardiogenic transcription factor, which would likely act downstream to STRA6-mediated RA signalling in human cardiogenesis. Conclusion Our study highlights the critical role of human-specific STRA6 progenitors for proper induction of vascular SMCs that is essential for normal OFT formation. Thus, these results shed light on novel and human-specific CHD mechanisms, driven by STRA6 mutations.
Carfilzomib, lenalidomide, and dexamethasone or lenalidomide alone as maintenance therapy after autologous stem-cell transplantation in patients with multiple myeloma (ATLAS): interim analysis of a randomised, open-label, phase 3 trial
Authors: Dominik Dytfeld, Tomasz Wróbel, Krzysztof Jamroziak, Tadeusz Kubicki, Paweł Robak, Adam Walter-Croneck, Jarosław Czyż, Agata Tyczyńska, Agnieszka Druzd-Sitek, Krzysztof Giannopoulos, Adam Nowicki, Tomasz Szczepaniak, Anna Łojko-Dankowska, Magdalena Matuszak, Lidia Gil, Bartosz Puła, Justyna Rybka, Maciej Majcherek, Lidia Usnarska-Zubkiewicz, Łukasz Szukalski, Agnieszka Końska, Jan Maciej Zaucha, Jan Walewski, Damian Mikulski, Olga Czabak, Tadeusz Robak, Oscar B Lahoud, Jeffrey A Zonder, Kent Griffith, Andrew Stefka, Ajay Major, Benjamin A Derman, Andrzej J Jakubowiak
Journal: The Lancet Oncology (2023)
Early Hyperprogression of Lymphoma Detected by 18F-FDG PET/CT After Chimeric Antigen Receptor T-Cell Therapy
Authors: Limeng He, Yan Deng, Ying Deng, Hongjun Xie, Wei Zhang
Journal: Clinical Nuclear Medicine (2023)

Abstract 18 F-FDG PET/CT plays important roles in the staging, treatment monitoring, and prognostic assessment of lymphoma. A 65-year-old woman with refractory large B-cell lymphoma underwent 18 F-FDG PET/CT imaging 35 days after a chimeric antigen receptor T-cell therapy. The images showed progression of the left maxillary lesion and additional involvement of the left facial subcutaneous tissue. Pathological examination of the left facial lesion led to a diagnosis of early hyperprogression of lymphoma.